C12orf48, Termed PARP-1 Binding Protein, Enhances Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activity and Protects Pancreatic Cancer Cells from DNA Damage

To identify novel therapeutic targets for aggressive and therapy-resistant pancreatic cancer, we had previously performed expression profile analysis of pancreatic cancers using microarrays and found dozens of genes trans-activated in pancreatic ductal adenocarcinoma (PDAC) cells. Among them, this study focused on the characterization of a novel gene C12orf48 whose overexpression in PDAC cells was validated by Northern blot and immunohistochemical analysis. Its overexpression was observed in other aggressive and therapy-resistant malignancies as well. Knockdown of C12orf48 by siRNA in PDAC cells significantly suppressed their growth. Importantly, we demonstrated that C12orf48 protein could directly interact with Poly(ADP-ribose) Polymerase-1 (PARP-1), one of the essential proteins in the repair of DNA damage, and positively regulate the poly(ADP-ribosyl)ation activity of PARP-1. Depletion of C12orf48 sensitized PDAC cells to agents causing DNA damage and also enhanced DNA damage-induced G2/M arrest through reduction of PARP-1 enzymatic activities. Hence, our findings implicate C12orf48, termed PARP-1 binding protein (PARPBP), or its interaction with PARP-1 to be a potential molecular target for development of selective therapy for pancreatic cancer. (C) 2010 Wiley-Liss, Inc.